Prostaglandin derivatives have various biological activities such as inhibition of platelet aggregation, a vasodilating activity lowering the blood pressure, suppression of the secretion of gastric acids, smooth muscle constriction, cytoprotection, and digresis and are useful for the treatment or prevention of cardiac infarction, angia, arteriosclerosis, hypertension, duodenal ulcers, oxytocia, abortion, etc.
Among these prostaglandin derivatives, as .DELTA..sup.8 type prostaglandin derivatives, there have been known the prostaglandin E.sub.1 affines of enol butyric acid esters of prostaglandin E.sub.1 (see Japanese Unexamined Patent Publication (Kokai) No. 5-213862).
On the other hand, it has been disclosed that 7-thiaprostaglandin E.sub.1 derivatives have a platelet aggregation inhibitory activity, hypotensive activity, and vasodilating activity and thereby an anti-thrombosis, anti-anginia, anti-cardiac infarction, anti-arteriosclerosis, and malignant tumor metathesis preventing activity and have an anti-tumor activity (see Japanese Unexamined Patent Publication (Kokai) No. 53-68753, Japanese Unexamined Patent Publication (Kokai) No. 58-110562, Japanese Unexamined Patent Publication (Kokai) No. 59-29661, Japanese Unexamined Patent Publication (Kokai) No. 60-185761, and Japanese Unexamined Patent Publication (Kokai) No. 61-204163). Further, these 7-thiaprostaglandin E.sub.1 derivatives are known to have effectiveness in the neuropathy in diabetes (see Japanese Unexamined Patent Publication (Kokai) No. 64-52721). Further, it has been reported that 7-thiaprostaglandin E.sub.1 derivatives have an activity suppressing thickening of the veins and an activity inhibiting migration of smooth muscle cells (see WO95/00150) and an activity inhibiting migration of THP-1 cells (see Japanese Unexamined Patent Publication (Kokai) No. 7-188025).
Corresponding enol ester derivatives (.DELTA..sup.8 type prostaglandin derivatives) are known for the 7-thiaprostaglandin E.sub.1 derivatives as well. These have been reported as having an activity suppressing thickening of veins and an activity inhibiting migration of THP-1 cells (see WO/19340).
The enol ester derivatives of these (7-thia)prostaglandin E.sub.1 derivatives have enol ester portions which easily hydrolyzed in the body due to the action of esterase and other enzymes and are believed to change to (7-this)prostaglandin E.sub.1 derivatives (9-oxo type). Therefore, these enol ester derivatives may be considered prodrugs of (7-thia)prostaglandin E.sub.1 derivatives.
The .DELTA..sup.8 type prostaglandins of the present invention differ from these enol ester derivatives in that they are compounds in which substituents not easily decomposed by the action of enzymes etc. are introduced at the 9-position. The inventors studied various compounds which were chemically stable in this way and further exhibited bioactivity in the .DELTA..sup.8 state and, as a result, found that these compounds have an inhibitory activity on cell migration caused by chemokines and thereby reached the present invention.
On the other hand, it has been reported that .DELTA..sup.8 type prostaglandin derivatives have a luteal recessive activity and an abortive activity (see DE3125271 or Japanese Unexamined Patent Publication (Kokai) No. 58-4763). The .DELTA..sup.8 -type prostaglandin derivatives shown here, however, are just derivatives where the 9-position substituent is hydrogen and the 7-position is methylene. It was not known at all that the compounds of the present invention have an inhibitory activity on the cell migration caused by chemokines.